Cyclic amine derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists

ABSTRACT

A novel series of substituted quinoxaline 2,3-diones useful as neuroprotective agents are taught. Novel intermediates, processes of preparation, and pharmaceutical compositions containing the compounds are also taught. The compounds are glutamate antagonists and are useful in the treatment of stroke, cerebral ischemia, or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, seizure disorders, pain, Alzheimer&#39;s, Parkinson&#39;s, and Huntington&#39;s Diseases.

CROSS-REFERENCE

This application is a continuation-in-part of U.S. application Ser. No.09/042,000 filed Mar. 17, 1998 now abandoned, which is a divisional ofU.S. application Ser. No. 08/474,877 filed Jun. 7, 1995 now U.S. Pat.No. 5,874,426.

BACKGROUND OF THE INVENTION

This invention is for novel glutamate receptor antagonists which are newcompounds of the 5,6,7,8-substituted quinoxaline 2,3-diones type. Thefused ring system is substituted at the a or b position by amino acidderivatives. The compounds are active as excitatory amino acid receptorantagonists acting at glutamate receptors, including either or bothN-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors such as theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptorand the kainate receptor. The invention also relates to the use of thosequinoxaline-2,3-diones as neuroprotective agents for treating conditionssuch as cerebral ischemia or cerebral infarction resulting from a rangeof phenomena, such as thromboembolic or hemorrhagic stroke, cerebralvasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatalasphyxia, anoxia such as from drowning, pulmonary surgery, and cerebraltrauma, as well as to treat chronic neurodegenerative disorders such asAlzheimer's Disease, Parkinsonism, and Huntington's Disease, and seizuredisorders and pain. Therefore, the compounds of the present inventionmay also be useful in the treatment of schizophrenia, epilepsy, anxiety,pain, and drug addiction. Excessive excitation by neurotransmitters cancause the degeneration and death of neurons. It is believed that thisdegeneration is in part mediated by the excitotoxic actions of theexcitatory amino acids (EAA) glutamate and aspartate at theN-methyl-D-aspartate (NMDA) receptor, theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor,and the kainate receptor. AMPA/kainate receptors may be referred tojointly as non-NMDA receptors. This excitotoxic action is consideredresponsible for the loss of neurons in cerebrovascular disorders such ascerebral ischemia or cerebral infarction resulting from a range ofconditions, such as thromboembolic or hemorrhagic stroke, cerebralvasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatalasphyxia, anoxia such as from drowning, pulmonary surgery, and cerebraltrauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease,and Huntington's Disease.

Several classes of quinoxalinedione derivatives have been disclosed asglutamate (EAA) receptor antagonists. For example, among excitatoryamino acid receptor antagonists recognized for usefulness in thetreatment of disorders are those that block AMPA receptors (Bigge C. F.and Malone T. C., Curr. Opin. Ther. Pat., 1993:951; Rogawski M. A.,TiPS, 1993;14:325). AMPA receptor antagonists have prevented neuronalinjury in several models of global cerebral ischemia (Li H. and BuchanA. M., J. Cerebr. Blood Flow Metab., 1993;13:933; Nellgard B. andWieloch T., J. Cerebr. Blood Flow Metab., 1992;12:2) and focal cerebralischemia (Bullock R., Graham D. I., Swanson S., McCulloch J., J. Cerebr.Blood Flow Metab., 1994;14:466; Xue D., Huang Z.-G., Barnes K., LesiukH. J., Smith K. E., Buchan A. M., J. Cerebr. Blood Flow Metab.,1994;14:251). AMPA antagonists have also shown efficacy in models foranalgesia (Xu X.-J., Hao J.-X, Seiger A., Wiesenfeld-Hallin Z., J.Pharmacol. Exp. Ther., 1993;267:140), and epilepsy (Namba T., MorimotoK., Sato K., Yamada N., Kuroda S., Brain Res., 1994;638:36; Brown S. E.,McCulloch J., Brain Res., 1994;641:10; Yamaguchi S. I., Donevan S. D.,Rogawski M. A., Epilepsy Res., 1993;15:179; Smith S. E., Durmuller N.,Meldrum B. S., Eur. J. Pharmacol., 1991;201:179). AMPA receptorantagonists have also demonstrated promise in chronic neurodegenerativedisorders such as Parkinsonism (Klockgether T., Turski L., Honore T.,Zhang Z., Gash D. M., Kurlan R., Greenamyre J. T., Ann. Neurol.,1993;34(4):585-593).

Excitatory amino acid receptor antagonists that block NMDA receptors arealso recognized for usefulness in the treatment of disorders. NMDAreceptors are intimately involved in the phenomenon of excitotoxicity,which may be a critical determinant of outcome of several neurologicaldisorders. Disorders known to be responsive to blockade of the NMDAreceptor include acute cerebral ischemia (stroke or cerebral trauma, forexample), muscular spasm, convulsive disorders, neuropathic pain, andanxiety, and may be a significant causal factor in chronicneurodegenerative disorders such as Parkinson's Disease (Klockgether T.,Turski L., Ann. Neurol., 1993;34:585-593), human immunodeficiency virus(HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS),Alzheimer's Disease (Francis P. T., Sims N. R., Procter A. W., Bowen D.M., J. Neurochem., 1993;60(5):1589-1604), and Huntington's Disease. (SeeLipton S., TINS, 1993;16(12):527-532; Lipton S. A., Rosenberg P. A., NewEng. J. Med., 1994;330(9):613-622; and Bigge C. F., Biochem. Pharmacol.,1993;45:1547-1561 and references cited therein.) NMDA receptorantagonists may also be used to prevent tolerance to opiate analgesia orto help control withdrawal symptoms from addictive drugs (Eur. Pat.Appl. 488,959A).

Copending U.S. Ser. No. 08/124,770 discloses glutamate receptorantagonist quinoxalinedione derivatives represented by the formula:##STR1## wherein A is a 5 to 7 atom containing ring having a nitrogenwhich may be substituted by hydrogen, alkyl, or CH₂ CH₂ OH. Thisapplication does not disclose or suggest compounds having the instantamino as substituents, or the requisite methodology to prepare the same.

Copending application U.S. Ser. No. 08/404,400 teaches glutamatereceptor antagonists which are quinoxalinediones of formula ##STR2## ora pharmaceutically acceptable salt thereof wherein R₁ is hydrogen, analkyl, or an alkylaryl;

X and Y are independently hydrogen, halogen, nitro, cyano,trifluoromethyl, COOH, CONR₄ R₅, SO₂ CF₃, SO₂ R₄, SONR₄ R₅, alkyl,alkenyl, (CH₂)_(z) CONR₄ R₅, (CH₂)_(z) COOR₄, or NHCOR₄, wherein R₄ andR₅ are independently hydrogen, alkyl having 1 to 6 carbon atoms,cycloalkyl, or alkylaryl, and z is an integer from 0 to 4;

R₂ is alkylCOOR₃, alkylamine, alkylquanidine, aryl, alkylaryl, COalkyl,COalkylaryl, CONR₃ alkyl, CONR₃ aryl, CONR₃ alkylaryl, CSNR₃ alkyl,CSNR₃ alkylaryl or a common amino acid moiety joined by an amide bond,wherein R₃ is hydrogen, alkyl, or alkylaryl; and

m and n are independently 0, 1, or 2 provided that m+n is >1.

This application does not disclose or suggest the compounds of theinstant invention having cyclic amines as substituents at the a- orb-positions nor the methodology to prepare them.

JP06228112-A discloses glutamate receptor antagonists which arequinoxaline-2,3(1H,4H)-dione derivatives of formula ##STR3## wherein R₁is H, NO₂, or CF₃ ; Ring A is a nitrogen-containing saturatedheterocyclic group which may contain sulfur or oxygen;

R₂ is H, OH, lower alkoxy, COOH, lower alkoxy carbonyl, NH₂, or loweralkoxy carbonyl-amino. This reference does not teach or suggest theinstant compounds which must be attached to the quinoxaline dione fusedring system by an alkylene.

WO 93/08188 covers a tricyclic quinoxalinedione of formula ##STR4## asuseful or selective antagonists of glutamate receptors.

European Patent Application 0627434 covers tricyclic quinoxalinedione ofFormula I below which are selective antagonists of glycine binding siteof the NMDA receptor ##STR5## wherein X represents hydrogen, alkyl,halogen, cyano, trifluoromethyl, or nitro;

R₁ represents hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl;

G represents --CONR₂ -- or --NR₂ CO--, wherein R₂ represents hydrogen oralkyl;

J represents an acidic group or a group which is convertible thereto invivo;

E represents a basic group or a group which is convertible thereto invivo;

Y represents a single bond, alkylene, alkenylene, substituted alkylene,or Y₁ --Q--Y₂, wherein Y₁ represents a single bond or alkylene, Y₂represents alkylene, and Q represents a heteroatom selected from oxygenor sulfur; and

Z represents alkylene.

WO 94/26747 discloses compounds of Formula I below as useful in thetreatment of cerebrovascular disorder ##STR6## wherein R₁ is hydrogen,alkyl or benzyl; X is O or NOR₂, wherein R₂ is hydrogen, alkyl, orbenzyl;

Y is N--R₄, wherein R₄ is hydrogen, OH, or alkyl;

n is 0 or 1;

R₆ is phenyl, naphthyl, thienyl, pyridyl, all of which may besubstituted one or more times with substituents selected from the groupconsisting of halogen;

CF₃, NO₂, amino, alkyl, alkoxy, and phenyl; and

A is a ring of 5 to 7 atoms fused with the benzo ring at the positionsmarked a and b.

The compounds of the instant invention differ from the art in that theyprovide noncoplanar compounds with greater solubility and, therefore,better ability to penetrate the blood-brain barrier. These are importantattributes in pharmaceuticals.

An object of this invention is to provide novel quinoxalinediones withcyclic amines at the a- or b-positions which function as antagonists.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by Formula I:##STR7## or a pharmaceutically acceptable salt thereof wherein R, R₁,R₂, R₃, R₄, R₅, and n are as described below.

The instant invention is also related to a pharmaceutical compositioncontaining the compound defined by Formula I in an amount effective totreat cerebrovascular disorders responsive to the blockade of glutamatereceptors (such as the α-amino-3-hydroxy-5-methyl-4-isoxazole propionicacid (AMPA) receptor and the kainate receptor), and a pharmaceuticallyacceptable carrier. Exemplary disorders responsive to such treatmentinclude cerebral ischemia caused by cerebral trauma, stroke,hypoglycemia, heart attack, and surgery; anxiety and schizophrenia; andchronic neurodegenerative disorders such as Huntington's Disease, ALS,Parkinsonism, and Alzheimer's Disease. The pharmaceutical composition ofthis invention may also be employed as an analgesic or the treatment ofepilepsy.

The invention further relates to a method of treating cerebrovasculardisorders responsive to antagonism of glutamate receptors NMDA byadministering a compound of above-defined Formula I in a unit dosageform.

Another object of this invention is to provide a method of treatingdisorders responsive to the antagonism of glutamate or aspartatereceptors in a human by administering a pharmaceutically effectiveamount of the 2,3-quinoxalinediones of this invention.

Another object of this invention is to provide novel methods ofpreparing the 2,3-quinoxalinediones.

A further object of this invention is directed to novel intermediatesuseful in the preparation of the 2,3-quinoxalinediones of thisinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Maximal Electroshock Time Course with Compound 1, Compound 2,and PNQX is1,4,7,8,9,10-hexahydro-7-methyl-6-nitro-pyrido[3,4-f]quinoxaline-2,3-dionein Mice IV

FIG. 2. Maximal Electroshock Dose-Response with PNQX, Compounds 4 and 1in Mice IV

DETAILED DESCRIPTION OF THE INVENTION

The substituted quinoxaline-2,3-diones of the instant invention arethose of Formula I ##STR8## or a pharmaceutically acceptable saltthereof wherein R is a cyclic amine;

n is an integer of from 1 to 4;

R₁ is hydrogen,

alkyl,

aralkyl,

carboxyalkyl,

phosphoroalkyl, or

phosphonoalkyl;

R₂ is hydrogen, hydroxy, or amino;

R₃ and R₄ are each independently

hydrogen,

alkyl,

cycloalkyl,

alkenyl,

halogen,

haloalkyl,

nitro,

cyano,

SO₂ CF₃,

CH₂ SO₂ R₆,

(CH₂)_(m) CO₂ R₆,

(CH₂)_(m) CONR₇ R₈,

(CH₂)_(m) SO₂ NR₇ R₈, or

NHCOR₆ wherein m is an integer of from 0 to 4, and R₆, R₇, and R₈ areeach independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl,or aralkyl;

R₅ is hydrogen,

alkyl,

alkenyl,

cycloalkyl,

halogen,

haloalkyl,

aryl,

aralkyl,

heteroaryl,

nitro,

cyano,

SO₂ CF₃,

(CH₂)_(m) CO₂ R₉,

(CH₂)_(m) CONR₉ R₁₀,

SONR₉ R₁₀, or

NHCOR₉ ;

m is an integer of from 0 to 4;

R₉ and R₁₀ are each independently hydrogen, alkyl, cycloalkyl,haloalkyl, or aralkyl; and

R₅ may be at the a-position and R--(CH₂)_(n) -- at the b-position on thering.

Preferred compounds are those of Formula I wherein R is a mono- orbi-cyclic ring unsubstituted or substituted by from 1 to 4 substituents,R is attached to the quinoxaline ring through N(--CH₂)_(n) and at the a-or b-position and

R is ##STR9## of from 4 to 7 atoms or ##STR10## of from 8 to 12 atomswherein R₁₁ is from 1 to 4 substituents independently selected from

hydrogen,

hydroxy,

hydroxyalkyl,

alkyl,

alkoxy,

alkoxyalkyl,

--NR₁₃ R₁₄,

aminoalkyl,

alkenyl,

alkynyl,

thiol,

thioalkyl,

alkylthioalkyl,

aryl,

aralkyl,

heteroaryl,

heteroaralkyl,

cycloalkyl,

--SO₂ R₁₅,

--SO₂ NR₁₃ R₁₄,

--(CH₂)_(n) SO₂ NR₁₃ R₁₄, and

--(CH₂)_(n) SO₂ R₁₅ ;

wherein R₁₃ and R₁₄ are independently selected from

hydrogen,

alkyl,

cycloalkyl,

heterocycloalkyl,

aralkyl, and

aryl;

R₁₅ is hydroxy, alkoxy, --NR₁₃ R₁₄, or haloalkyl;

R₁₁ may be 2 substituents attached at the same carbon;

X and Y are each independently

carbon which is substituted by hydrogen, halogen, haloalkyl, alkyl,alkoxy, alkoxyalkyl, NR₁₃ R₁₄, aminoalkyl, aralkyl, aryl, heteroaryl,heteroaralkyl, cycloalkyl, heterocycloalkyl, hydroxy, and hydroxyalkyl,

--O--,

--S--,

--SO--,

--SO₂ --,

--NR₁₆ --,

wherein R₁₆ is alkyl, hydrogen, aralkyl, heteroaralkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, --C(O)OR₁₇, --C(O)R₁₇, --SO₂R₁₈, --SO₂ NR₁₉ R₂₀, --CH₂ SO₂ R₁₈, --CH₂ SO₂ NR₁₉ R₂₀,

wherein R₁₇ is alkyl, aralkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl;

R₁₈ is alkyl, aralkyl, hydroxyl, or alkoxy;

R₁₉ and R₂₀ are each independently hydrogen and alkyl.

Bicyclic structures encompassed in this invention include spiro ringstructures, wherein both ends of a second ring are attached to the samecarbon unit on the parent ring.

For monocyclic and bicyclic structures wherein X or Y represent a carbonatom, the structure may also include an integral double bond.

More preferred are those of Formula I wherein

R is ##STR11## of from 4 to 7 atoms where X is

carbon substituted by hydrogen, haloalkyl, alkyl, alkoxy, alkoxyalkyl,NR₁₃ R₁₄, aminoalkyl, cycloalkyl, heterocycloalkyl, hydroxy, andhydroxyalkyl,

--O--,

--NR₁₆ --, and

--C(O)--;

R₁₁ is absent,

hydrogen,

alkyl,

alkoxy,

alkoxyalkyl,

NR₁₃ R₁₄,

aminoalkyl,

aralkyl,

aryl,

heteroaryl,

heteroaralkyl,

cycloalkyl,

heterocycloalkyl,

hydroxy, or

hydroxyalkyl,

R₁₁ may also represent two independent alkyl substituents to form agem-dialkyl arrangement,

where X represents carbon, an integral double bond may be locatedbetween the C₃ and C₄ carbons of 5- to 7-membered rings.

Still more preferred are those of Formula I wherein R is ##STR12## offrom 4 to 7 atoms where X is

carbon substituted by hydrogen, alkyl, NR₁₃ R₁₄, aminoalkyl, cycloalkyl,and heterocycloalkyl,

--O--,

--NR₁₆ --, and

--C(O)--;

R¹¹ is absent,

hydrogen,

hydroxy,

hydroxyalkyl,

alkyl,

alkoxy,

alkoxyalkyl,

--NR₁₃ R₁₄,

aminoalkyl,

cycloalkyl, or

heterocycloalkyl;

R₁₁ may also represent two independent alkyl substituents to form agem-dialkyl arrangement,

where X represents carbon, an integral double bond may be locatedbetween the C₃ and C₄ carbons of 5- to 7-membered rings.

R₁ is hydrogen;

R₂ is hydrogen or hydroxy;

R₃ and R₄ are each independently

hydrogen,

alkyl, or

nitro;

R₅ is hydrogen,

alkyl,

cycloalkyl,

halo, or

nitro.

Most preferred are selected from

6-Methyl-5-pyrrolidin-1-ylmethyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-5-(2-methyl-pyrrolidin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

5-(2,5-Dimethyl-pyrrolidin-1-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-7-nitro-5-piperidin-1-ylmethyl-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-5-(2-methyl-piperidin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-5-(4-methyl-piperidin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

5-(3,5-Dimethyl-piperidin-1-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

5-(3-Azaspiro[5.5]undec-3-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

5-(1,4-Dioxa-8-azaspiro[4,5]dec-8-ylmethyl)-6-methyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-5-morpholin-4-ylmethyl-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-5-(4-methyl-piperazin-1-ylmethyl)-7-nitro-1,4-dihydroquinoxaline-2,3-dione,

5-Azepan-1-ylmethyl-6-methyl-7-nitro-1,4-dihydroqinoxaline-2,3-dione,

6-Methyl-7-nitro-5-(octahydroquinolin-1-ylmethyl)-1,4-dihydroquinoxaline-2,3-dione,

6-Methyl-7-nitro-5-(octahydroisoquinolin-2-ylmethyl)-1,4-dihydroquinoxaline-2,3-dione,and

6-Chloro-7-nitro-5-piperidin-1-ylmethyl-1,4-dihydro-quinoxaline-2,3-dionesulfate salt.

Other preferred compounds of the invention are those of Formula Iwherein R is ##STR13## of from 8 to 12 atoms; X and Y are eachindependently as described above;

R₁₁ is absent,

hydrogen,

alkyl,

alkoxy,

alkoxyalkyl,

NR₁₃ R₁₄,

aminoalkyl,

aralkyl,

aryl,

heteroaryl,

heteroaralkyl,

cycloalkyl,

heterocycloalkyl,

hydroxy, and

hydroxyalkyl;

R₁ is hydrogen;

R₂ is hydrogen or hydroxy;

R₃ and R₄ are each independently

hydrogen,

alkyl, and

nitro;

R₅ is hydrogen,

alkyl,

cycloalkyl,

halogen, and

nitro.

The compounds of Formula I are capable of further formingpharmaceutically acceptable acid addition salts. These forms are withinthe scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from nontoxicorganic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, isethionate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,"Pharmaceutical Salts," Journal of Pharmaceutical Science,1977;66:1-19).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention may exist as a mixtureof cis and trans isomers or as the individual cis and trans isomers or Rand S stereoisomers. The mixture of isomers as well as the individualisomers are intended to be encompassed within the scope of the presentinvention.

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon radical having from 1 to 6 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "carboxyalkyl" means alkyl as above and attached to a carboxygroup.

The term "phosphoroalkyl" means alkyl as above and attached to aphosphoro group.

The term "phosphonoalkyl" means alkyl as above and attached to aphosphono group.

The term "alkenyl" means a straight or branched unsaturated hydrocarbonradical having from 3 to 6 carbon atoms and includes, for example,2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl,3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

Alkynyl means a straight or branched unsaturated hydrocarbon radical offrom 2 to 6 carbon atoms and includes but is not limited to ethynyl,2,3-propynyl, 1,2-propynyl, and 3,4-butynyl.

"Alkoxy" is O-alkyl of from 1 to 6 carbon atoms as defined above for"alkyl".

The term "aryl" means an aromatic radical which is a phenyl group, aphenyl group substituted by 1 to 4 substituents selected from alkyl asdefined above, alkoxy as defined above, thioalkoxy as defined above,hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined abovefor alkyl, dialkylamino as defined for alkyl, or 1,3-benzodioxol-5-yl.

The term "aralkyl" means aryl and alkyl as defined above and includesbut is not limited to benzyl, 2-phenylethyl, and 3-phenylpropyl; apreferred group is phenyl.

The term "heteroaryl" means a heteroaromatic radical which is 2-, 3-, or4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, isoquinolines,quinolines, imidazolines, pyrroles, indoles, and thiazoles.

"Halogen" is fluorine, chlorine, bromine, or iodine.

The term "haloalkyl" means halogen and alkyl as defined above, forexample, but not limited to, trifluoromethyl and trichloromethyl.

"Alkylaryl" means aryl as defined above and alkyl as defined above, forexample, but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; apreferred group is benzyl.

The term "heterocycloalkyl" means a nonaromatic ring with from 4 to 7members, with up to 4 heteroatoms for example, N, O, and S.

Spiro rings include but are not limited to 5- to 7-membered carbocyclicor heterocyclic ring with up to 4 heteroatoms.

R in Formula I may be defined as follows. These groups are merelyillustrative of the invention. ##STR14##

The compounds of the invention exhibit valuable biological propertiesbecause of their strong excitatory amino acid (EAA) antagonizingproperties at one of several binding sites on glutamate receptors: theAMPA ((RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (or kainicacid) binding site on AMPA (non-NMDA) receptors or the glycine site ofNMDA receptors.

The compounds of the present invention exhibit binding affinity for theAMPA receptors measured as described in Honore T., et al., NeuroscienceLetters, 1985;54:27-32. Preferred compounds demonstrate IC₅₀ values <100μM in this assay. The compounds of the present invention exhibit bindingaffinity for the kainate site (non-NMDA receptor) measured as describedin London E. D. and Coyle J., Mol. Pharmacol., 1979;15:492. Thecompounds of the present invention exhibit binding affinity for theglycine site of the NMDA receptor measured as described in Jones S. M.,et al., Pharmacol. Methods, 1989;21:161. To measure functional AMPAantagonist activity, the effects of the agent on AMPA-induced neuronaldamage in primary cortical neuronal cultures was examined usingtechniques similar to those outlined by Koh J.-Y., et al., J. Neurosci,1990;10:693. In addition, the neuronal damage produced by long-termexposure to 100 μM AMPA may be measured by the release of the cytosolicenzyme lactate dehydrogenase (LDH).

Selected compounds of the present invention were tested by one or moreof the above-described assays. The data obtained in the assays is setforth in Tables 1-4 below. The IC₅₀ values set forth in Tables 1-4 are ameasure of the concentration (μM) of the test substance which inhibits50% of an induced release from the tested receptors.

                  TABLE 1                                                         ______________________________________                                        Quinoxalinediones With Cyclic Amine                                             #STR15##                                                                                           IC.sub.50 μM                                        Compound    Structure        AMPA    KA                                       ______________________________________                                          6-Methyl-5-pyrrolidin-  1-ylmethyl-7-nitro-  1,4-dihydro-  quinoxaline-2                                         ,3-dione                                                                        0.22 4.52                                 - 6-Methyl-5-(2-methyl-  pyrrolidin-1-ylmethyl)-  7-nitro-1,4-dihydro-                                           quinoxaline-2,3-dione                                                          0.37 6.11                                 - 5-(2,5-Dimethyl-  pyrrolidin-1-ylmethyl)-  6-methyl-7-nitro-                                                  1,4-dihydro-  quinoxaline-2,3-dione                                             0.74 2.84                                 - 6-Methyl-5-(piperidin-  1-ylmethyl)-  7-nitro-1,4-dihydro-  quinoxali                                         ne-2,3-dione                                                                    0.29 4.11                                 - 6-Methyl-5-(2-methyl-  piperidin-1-ylmethyl)-  7-nitro-1,4-dihydro-                                           quinoxaline-2,3-dione                                                           0.49 8.28                                 - 6-Methyl-5-(4-methyl-  piperidin-1-ylmethyl)-  7-nitro-1,4-dihydro-                                           quinoxaline-2,3-dione                                                           0.42 9.95                                 - 5-(3,5-Dimethyl-  piperidin-1-ylmethyl)-  6-methyl-7-nitro-  dione                                              #STR22##                                  - 1,4-dihydro-  quinoxaline-2,3-5-(3-  Azaspiro[5,5]undec-3-  ylmethyl)                                         -6-methyl-7-  nitro-1,4-dihydro-                                              quinoxaline-2,3-dione                                                           0.486 6.54                                - 5-(1,4-Dioxa-8-  azaspiro[4,5]dec-8-  ylmethyl)-6-methyl-7-                                                   nitro-1,4-dihydro-  quinoxaline-2,3-d                                         ione                                                                            #STR24##                                  - 6-Methyl-5-(morpholin-  1-ylmethyl)-7-nitro-  1,4-dihydro-  quinoxali                                         ne-2,3-dione                                                                    0.572 9.083                               - 6-Methyl-5-(4-methyl-  piperazin-1-ylmethyl)-  7-nitro-1,4-dihydro-                                           quinoxaline-2,3-dione                                                           2.47 13.2                                 - 5-(Azepan-1-yl-  methyl)-6-methyl-7-  nitro-1,4-dihydro-  quinoxaline                                         -2,3-dione                                                                      0.899 3.695                               - 6-Methyl-7-nitro-5-  (octahydroquinolin-1-  ylmethyl)-1,4-dihydro-                                            quinoxaline-2,3-dione                                                           #STR28##                                  - 6-Methyl-7-nitro-5-  (octahydroisoquinolin-  2-ylmethyl)-1,4-                                                 dihydroquinoxaline-2,3-  dione                                                 ##STR29##                               ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________    o-Nitroaniline Derivatives                                                                                    IC.sub.50 μM                                                               MS (CI)                                         Compound Structure Yield % M + 1                                            __________________________________________________________________________      3-Methyl-6-nitro-2-  pyrrolidin-1-ylmethyl-  phenylamine                                                  80 236 #                                           - 3-Methyl-2-(2-methylpyrrol-  idin-1-ylmethyl)-6-nitro-  phenylamine                                    62 250 #                                           - 2-(2,5-Dimethyl-  pyrrolidin-1-ylmethyl)-3-  methyl-6-nitro-phenylami                                ne                                                                              65 264 #                                           - 3-Methyl-6-nitro-2-  piperidin-1-ylmethyl-  phenylamine                                                84 250 #                                           - 3-Methyl-2-(2-methyl-  piperidin-1-ylmethyl)-6-  nitro-phenylamine                                     49 264 #                                           - 3-Methyl-2-(4-methyl-  piperidin-1-ylmethyl)-6-  nitro-phenylamine                                     74 264 #                                           - 2-(3,5-Dimethyl-piperidin-  1-ylmethyl)-3-methyl-6-  nitro-phenylamin                                e                                                                               76 278 #                                           - 2-(3-Azaspiro[5.5]undec-  3-ylmethyl)-3-methyl-6-  nitro-phenylamine                                   93 318 #                                           - 2-(1,4-Dioxa-8-azaspiro  [4,5]dec-8-ylmethyl)-3-  methyl-6-nitro-phen                                ylamine                                                                         71 308 #                                           - 3-Methyl-2-morpholin-4-  ylmethyl-6-nitro-phenyl-  amine                                                43* 252                                           - 3-Methyl-2-(4-methyl-  piperazin-1-ylmethyl)-6-  nitro-phenylamine                                     77 265 #                                           - 2-Azepan-1-ylmethyl-3-  methyl-6-nitro-phenylamine                                                     79 264 #                                           - 3-Methyl-6-nitro-2-  (octahydroquinolin-1-  ylmethyl)-phenylamine                                      51 304 #                                           - 3-Methyl-6-nitro-2-  (octahydroisoquinolin-2-  ylmethyl)-phenylamine                                   80 304##                                        __________________________________________________________________________     *Prepared via Scheme 2 (PBr.sub.3)                                       

                                      TABLE 3                                     __________________________________________________________________________    Quinoxaline-2, 3-diones                                                                                       IC.sub.50 μM                                                                   MS (CI)                                     Compound Yield % M + 1                                                      __________________________________________________________________________      6-Methyl-5-pyrrolidin-1-  ylmethyl-1,4-dihydro-  quinoxaline-2,3-dione                                            69 260 #                                   - 5-(2-Methyl-pyrrolidin-1-  ylmethyl)-1,4-dihydro-  quinoxaline-2,3-di                                        one                                                                             76 274 #                                   - 5-(2,5-Dimethyl-  pyrrolidin-1-ylmethyl)-6-  methyl-1,4-dihydro-                                             quinoxaline-2,3-dione                                                           52 288 #                                   - 6-Methyl-5-piperidin-1-  ylmethyl-1,4-dihydro-  quinoxaline-2,3-dione                                          64 274 #                                   - 6-Methyl-5-(2-methyl-  piperidin-1-ylmethyl)-1,4-  dihydro-quinoxalin                                        e-2,3-  dione                                                                   63 288 #                                   - 6-Methyl-5-(4-methyl-  piperidin-1-ylmethyl)-  1,4-dihydro-quinoxalin                                        e-  2,3-dione                                                                   66 289 #                                   - 5-(3,5-Dimethyl-piperidin-  1-ylmethyl)-6-methyl-1,4-  dihydro-quinox                                        aline-2,3-  dione                                                               59 302 #                                   - 5-(3-Aza-spiro[5.5]undec-  3-ylmethyl)-6-methyl-1,4-  dihydro-quinoxa                                        line-2,3-  dione                                                                69 342 #                                   - 5-(1,4-Dioxa-8-aza-  spiro[4,5]dec-8-ylmethyl)-  6-methyl-1,4-dihydro                                        -  quinoxaline-2,3-dione                                                        51 332 #                                   - 6-methyl-5-morpholin-  4-ylmethyl-7-nitro-1,4-  dihydro-quinoxaline-2                                        ,3-  dione                                                                      67 276 #                                   - 6-Methyl-5-(4-methyl-  piperazin-1-ylmethyl)-1,4-  dihydro-quinoxalin                                        e-2,3-  dione                                                                   41 289 #                                   - 5-Azepan-1-ylmethyl-6-  methyl-1,4-dihydro-  quinoxaline-2,3-dione                                             39 288 #                                   - 6-Methyl-5-(octahydro-  quinolin-1-ylmethyl)-1,4-  dihydro-quinoxalin                                        e-2,3-  dione                                                                   79 328 #                                   - 6-Methyl-5-(octahydro-  isoquinolin-2-ylmethyl)-  1,4-dihydro-quinoxa                                        line-  2,3-dione                                                                76 328##                                __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    7-Nitro-quinoxaline-2,3-diones                                                                                IC.sub.50 μM                                                                   MS (CI)                                     Compound Yield % M + 1                                                      __________________________________________________________________________      6-Methyl-5-pyrrolidin-1-  ylmethyl-7-nitro-1,4-  dihydroquinoxaline-2,3-                                        dione                                                                           92 305 #                                   - 6-Methyl-5-(2-methyl-  pyrrolidin-1-ylmethyl)-  7-nitro-1,4-dihydro-                                          quinoxaline-2,3-dione                                                          47 319 #                                   - 5-(2,5-Dimethyl-pyrrolidin-1-  ylmethyl)-6-methyl-7-nitro-  1,4-dihyd                                        roquinoxaline-2,3-  dione                                                       41 331 #                                   - 6-Methyl-7-nitro-5-piperidin-  1-ylmethyl-1,4-dihydro-  quinoxaline-2                                        ,3-dione                                                                        84 319 #                                   - 6-Methyl-5-(2-methyl-  piperidin-1-ylmethyl)-7-  nitro-1,4-dihydroqui                                        noxaline-  2,3-dione                                                            77 333 #                                   - 6-Methyl-5-(4-methyl-  piperidin-1-ylmethyl)-7-  nitro-1,4-dihydroqui                                        noxaline-  2,3-dione                                                            68 333 #                                   - 5-(3,5-Dimethyl-piperidin-1-  ylmethyl)-6-methyl-7-nitro-  1,4-dihydr                                        oquinoxaline-2,3-  dione                                                        79 347 #                                   - 5-(3-Azaspiro[5.5]undec-3-  ylmethyl)-6-methyl-7-nitro-  1,4-dihydroq                                        uinoxaline-2,3-  dione                                                          91 387 #                                   - 5-(1,4-Dioxa-8-azaspiro[4,5]  dec-8-ylmethyl)-6-methyl-7-  nitro-1,4-                                        dihydroquinoxaline-  2,3-dione                                                  29 377 #                                   - 6-Methyl-5-morpholin-4-  ylmethyl-7-nitro-1,4-  dihydroquinoxaline-2,                                        3-dione                                                                         56 321 #                                   - 6-Methyl-5-(4-methyl-  piperazin-1-ylmethyl)-7-  nitro-1,4-dihydroqui                                        noxaline-  2,3-dione                                                            64 334 #                                   - 5-Azepan-1-ylmethyl-6-methyl-  7-nitro-1,4-dihydro-  qinoxaline-2,3-d                                        ione                                                                            59 333 #                                   - 6-Methyl-7-nitro-5-  (octahydroquinolin-1-  ylinethyl)-1,4-dihydro-                                          quinoxaline-2,3-dione                                                           59 373 #                                   - 6-Methyl-7-nitro-5-  (octahydroisoquinolin-2-  ylmethyl)-1,4-dihydro-                                          quinoxaline-2,3-dione                                                         88 373##                                __________________________________________________________________________

Additionally, as a preliminary indicator of in vivo CNS activity relatedto anticonvulsant activity and potential neuroprotection, a maximalelectroshock assay in CF-1 strain mice (20-25 g) was performed withcorneal electrodes by conventional methods as described previously(Krall, et al., Epilepsia, 1988;19:409-428). The compounds of thisinvention generally demonstrated ED₅₀ values of <50 mg/kg.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the maximal electroshock time course with Compounds 1 and 4of the instant invention and the standard PNQX in ten mice given in adose of 30 mg/kg IV. The graph is the % of mice protected versus thetime in minutes. The ▪ is PNQX at 3 mg/kg IV, the ▴ is Compound 1, andthe  is Compound 4.

FIG. 2 shows the maximal electroshock dose-response with PNQX andCompounds 1 and 4 of the instant invention in ten mice. The ▪ is PNQXwith an ED₅₀ of 0.5 mg/kg IV; 30 seconds,  is Compound 4 with an ED₅₀of 12 mg/kg IV; 60 seconds, and ▴ is Compound 1 with an ED₅₀ of 14 mg/kgIV; 180 seconds.

In particular see FIGS. 1 and 2 wherein, when compared with thestandard, a tricyclic quinoxaline-dione AMPA antagonist (PNQX),Compounds 1 and 4 of the instant invention show surprising results.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprises conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Tablets containing 10 mgof active ingredients or, more broadly, 0.1 to 100 mg per tablet, andaccordingly suitable representative unit dosage forms.

Solid forms of pharmaceutical compositions for PO administration andinjectable solutions are preferred.

The compounds of this invention are extremely useful in the treatment ofcentral nervous system disorders related to their biological activity.The compounds of this invention may accordingly be administered to asubject, including a human, in need of treatment, alleviation, orelimination of an indication associated with the biological activity ofthe compounds. This includes especially excitatory amino-acid-dependentpsychosis, excitatory amino-acid-dependent anoxia, excitatoryamino-acid-dependent ischemia, excitatory amino-acid-dependentParkinsonism, excitatory amino-acid-dependent convulsions, andexcitatory amino-acid-dependent migraine. Suitable dosage ranges are 0.1to 1000 mg daily, 10 to 50 mg daily, and especially 30 to 100 mg daily,dependent as usual upon the exact mode of administration, form in whichadministered, the indication toward which the administration isdirected, the subject involved, and the body weight of the subjectinvolved, and further, the preference and experience of the physician orveterinarian in charge.

The schemes and examples which follow are intended as an illustration ofcertain preferred embodiments of the invention, and no limitation of theinvention is implied. ##STR72##

Step (a) of General Scheme I above involves reacting nitroanilinederivative of Formula (1) with amine as depicted in Formula (2) in thepresence of triaryiphosphine, preferably triphenyiphosphine and diesterof diazodicarboxylate, preferably diethyldiazodicarboxylate in asolution of a hydrocarbon solvent like benzene or ether solvent likeTHF, preferably benzene at temperatures around 5° C. The reactionmixture is stirred for 2 to 16 hours and monitored by TLC (SiO₂, pet.ether:EtOAc, 1:1). Solvent is evaporated under reduced pressure andproduct isolated by column chromatography (SiO₂, mixture of pet. etherand EtOAc).

Step (b) involves reducing the nitroaniline derivative of Formula (3)via hydrogenolysis (H₂, around 50 psi) in the presence of a catalystlike Ra Ni or Pd/C, preferably Ra Ni in a hydroxylated solvent likemethanol. The catalyst is filtered off and the filtrate evaporated togive the o-phenylenediamine derivative, which is used in the next stepwithout additional purification.

Step (c) involves reacting the o-phenylenediamine derivative as shown inFormula (4) with oxalic acid derivative like dimethyl oxalate in ahydroxylated solvent like methanol at refluxing temperatures for 12 to24 hours. The reaction mixture is partially evaporated to give crudeproduct, which is purified by crystallization.

Step (d) involves reacting the quinoxaline-2,3-dione derivative shown inFormula (5) with a nitrating mixture, preferably KNO₃ and sulfuric acidor TFA at temperatures ranging from 0° C. to room temperature. Thereaction mixture is poured over ice, neutralized with alkali, preferablyammonium hydroxide, and the solid obtained is purified bycrystallization or column chromatography (SiO₂, pet. ether:EtOAcmixture). ##STR73##

Step (a) in General Scheme II above involves bromination of thenitroaniline derivative shown in formula (1) with brominating agentslike CBr₄ /PPh₃ or PBr₃ in a solvent like ether. The volatile materialsare evaporated under reduced pressure and the crude product is useddirectly in step (b) or purified by column chromatography (SiO₂, pet.ether:EtOAc mixture).

Step (b) involves reacting the benzyl bromide derivative shown inFormula (2) with appropriate amino compound shown in Structure (3) inthe presence of a base like triethylamine in an ether solvent like THFat temperatures ranging from 10-60° C. The reaction mixture isevaporated to under reduced pressure and quenched with water. Productextracted with a solvent like EtOAc. Final product is purified by columnchromatography (SiO₂, pet. ether:EtOAc).

Formula (3) in Scheme II can be further derivatized to 4, 5, and 6 inScheme I. ##STR74##

Step (a) in General Scheme III involves reacting an aminoalcohol asshown in formula (1) with phosgene equivalent, preferably phosgene intoluene solution, in the presence of a tertiary base like triethylaminein an ether solvent like tetrahydrofuran. The reaction carried out understirring at temperatures ranging from 0-40° C. for 12 to 20 hours,preferably 16 hours. Reaction was subjected to aqueous work-up andproduct extracted in EtOAc. EtOAc extracts were worked with water anddried over MgSO₄. Crude product was purified via crystallization usingpet. ether:EtOAc mixture of solvents.

Step (b) involves reacting the cyclic carbamate as shown in formula (2)with a halogenating agent like bromine, preferably bromine in acidicmixture like TFA/AcOH at around 10° C. under stirring. Reaction mixturewas poured in ice water after stirring for about 2 hours at roomtemperature. The product obtained was used further without additionalpurification.

Step (c) involves nitrating the cyclic carbamate shown in formula (3)with nitrating mixture, preferably KNO₃ /conc. H₂ SO₄ at temperaturesbetween -5 to 5° C., preferably 0° C. under stirring. The reactionmixture allowed to warm to room temperature and stirred for 2 to 16hours, preferably 14 hours, and poured over ice. The precipitateobtained was filtered and used in next step.

Step (d) involves animation of the cyclic carbamate shown in formula (4)using the appropriate amine with or without a solvent. A solvent can beDMF, N-methylformamide, triethyamine, but preferably the amine itself,when amine is a liquid. The reaction mixture was heated to 100-150° C.,preferably the boiling point of the amine, if below 150° C. Volatilematerials are removed under vacuo and the final product purified bychromatography (SiO₂, using pet. ether:EtOAc mixture in rangingproportions as the solvent).

These general experimental schemes cover most of the final products ofthe invention. Others are made by known experimental procedures.

The above methodologies can be used to synthesize cyclic amines whichare monocycles or bicycles. ##STR75## (2-Amino-6-methyl-phenyl)-methanol

2-Amino-6-methyl-benzoic acid (45 g, 300 mmol) was suspended in etherand LAH (13.26 g, 350 mmol), was added portionwise. The reaction mixturewas stirred at room temperature for 4 hours and quenched with aqueousNH₄ Cl. Reaction mixture was filtered, and the filtrate was extractedwith ether (3×200 mL). The wet cake was also washed with ether (200 mL),and the ether solutions were pooled together and washed with water (200mL) and dried over MgSO₄. Solvent was evaporated to give a crystallineproduct (19.04 g, 46%), mp 78-81° C.; MS (CI): M+1=138. ##STR76## AceticAcid 2-acetylamino-6-methyl-benzyl ester

A solution of (2-amino-6-methyl-phenyl)-methanol (19.04 g, 138.9 mmol)in acetic anhydride (100 mL) was heated to 50° C. for 2 hours. Excessacetic anhydride removed under vacuum to give a pale brown solid,crystallized from CCl₄ (29.8 g, 97%), mp 118-119° C. (rep. 118-118.5°C.); MS (CI): M+1=222. ##STR77## Acetic Acid2-acetylamino-6-methyl-3-nitro-benzyl ester

To a solution of acetic acid 2-acetylamino-6-methyl-benzyl ester inacetic acid (400 mL) nitric acid (60%, 16 mL) was added dropwise keepingtemperature below 5° C., under stirring. Reaction mixture was stirredfor additional 2 hours at room temperature and poured in ice water andstirred for 0.5 hours. Brown oil separated which on treatment with ethylacetate (50 mL) gave buff needles, (7.65 g, 18.5%), mp 148-149° C. (rep.147-148° C.); MS (CI): M+1=267. ##STR78##(2-Amino-6-methyl-3-nitro-phenyl)-methanol

Acetic acid 2-acetylamino-6-methyl-3-nitro-benzyl ester (7 g, 26.2 mmol)was dissolved in methanolic KOH (0.5N). The solution was evaporatedafter 1 hour of stirring at room temperature. Product was extracted inEtOAc (150 mL), washed with water and brine, and dried (MgSO₄).Evaporation of the solvent gave orange needles (4.45 g, 93.4%), mp134-136° C. (rep. 135-136° C.). ##STR79## General Method for thePreparation of Cyclic aminomethyl-3-methyl-6-nitro-phenylamine

To a suspension of (2-amino-6-methyl-3-nitro-phenyl)-methanol (1 eq.)and PPh₃ (1.5 eq.), and cyclic amine (1.5 eq.) in benzene (10 mL),diethyl azodicarboxylate (DEAD) (1.5 eq.) was added under nitrogen and5° C. The reaction mixture was allowed to warm to room temperature andstirred for 2 hours. The dark reaction mixture was concentrated undervacuum, and the residue was chromatographed over silica gel(hexanes:ethyl acetate, 95:5 to 75:25) to give the desired product.Various derivatives synthesized are listed in Table 2 above. ##STR80##General Method for Preparation of3-dialkylamino-methyl-4-methyl-benzene-1,2-diamine

A solution of 2-(disubstituted aminomethyl-3-methyl-6-nitro-phenylamine(1 eq., approx. 5 mmol) in methanol (75 mL) was hydrogenated (H₂, 50psi) in a Parr apparatus. The reaction was monitored by TLC (SiO₂ l pet.ether:EtOAc, 1:1) and filtered on completion. The filtrate wasconcentrated, and the product obtained was used further withoutadditional purification. ##STR81## General Method for the Preparation of5-dialkylamino methyl-6-methyl-1,4-dihydro-quinoxaline-2,3-dione

A solution of 3-dialkylaminomethyl-4-methyl-benzene-1,2-diamine (1 eq.)and dimethyl oxalate (1.5 eq.) in methanol (35 mL) was heated to refluxfor 16 hours. The reaction mixture was partially evaporated to give theproduct as a solid, which was used further without additionalpurification. The compounds synthesized are listed in Table 3 above.##STR82## 2-Bromomethyl-3-methyl-6-nitro-phenylamine

To a solution of 2-amino-6-methyl-3-nitro-phenyl-methanol (1.09 g, 62mol) in ether (10 HL) and THF (25 mL), PBr₃ (3.24 g, 12 mmol) wasadded. Reaction mixture was heated to reflux and after 5 hoursevaporated to dryness. Crude product was passed through a short SiO₂column using pet. ether:EtOAc (1:1) as eluent. (Yield: 1.2 g, 82%); HNMRCDCl₃ : 2.42 (s, 3H), 4.53 (s, 2H), 6.61 (d, 1H, J=8.8 Hz), 8.07 (d, 1H,J=8.8 Hz). ##STR83## 3-Methyl-2-morpholin-4-ylmethyl-6-nitro-phenylamine

To a solution of 2-bromomethyl-3-methyl-6-nitro-phenylamine (1.2 g, 4.9mmol) in THF (20 mL), morpholine (2 g, 24 mmol) was added. Reactionmixture was stirred for 16 hours at room temperature, and thebuff-colored precipitate was filtered, washed, and dried. (Yield: 0.655g, 43%); MS(CI): M+1=252.

The intermediate 3-methyl-2-morpholin-4-ylmethyl-6-nitro-phenylamine wasfurther converted to the 7-nitro-quinoxaline-2,3-dione analog asindicated in Scheme 1 above. ##STR84## General Method for thePreparation of 5-dialkylaminomethyl-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione

To a solution of5-dialkylaminomethyl-6-methyl-1,4-dihydro-quinoxaline-2,3-dione (1 eq.,approx. 2-5 mmol) in concentrated H₂ SO₄ (5 mL) or TFA (5 mL), KNO₃ wasadded at 0° C. under stirring. In case of H₂ SO₄ as a solvent, reactionmixture was poured over ice, neutralized with alkalai, and the solidobtained crystallized or passed through a column (SiO₂, CHCl₃, and CHCl₃:MeOH 95:5) to give pure product. With TFA as a solvent, excess TFA wasevaporated (<35° C.) and solid obtained purified as mentioned aboveafter neutralization with NH₃.

The compounds synthesized are listed in Table 4 above. ##STR85##5-Methyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

To a solution of (2-amino-6-methyl-phenyl)-methanol (2.74 g, 20 mmol)and triethylamine (4.04 g, 40 mmol) in THF (150 mL), phosgene (12.5%solution in toluene, 17.42 g, 22 mmol) was added dropwise at 0° C.Reaction mixture was allowed to warm to room temperature and stirred for16 hours. Water (150 mL) was added under stirring, followed by EtOAc(2×100 mL). EtOAc extracts were washed with water and brine and driedover MgSO₄. The product (buff solid) was crystallized from EtOAc:pet.ether mixture. (Yield: 2.37=73%); (mp 222-226° C.); MS(CI): M+1=163.##STR86## 6-Bromo-5-methyl-1,4-dihydro-benzo[d][1,3]oxazine-2-one

To a solution of 5-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.695g, 4.3 mmol) in acetic acid (5 mL), Br₂ (0.805 g, 5 mmol) solution inTFA (5 mL)+acetic acid (5 mL) was added at 10° C. Reaction mixture wasstirred for 2 hours and poured over ice water. Yellow precipitate wasfiltered and dried at 120° C. (Yield: 0.941 g=90%); MS(CI): M+1=243;M+2=244. ##STR87##6-Bromo-5-methyl-8-nitro-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of 6-bromo-5-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.726 g, 3 mmol) in conc. H₂ SO₄ (4 mL), KNO₃ (0.303 g, 3 mmol) wasadded at 0° C. Reaction mixture stirred 14 hours and poured over crushedice. Yellow precipitate was obtained, which was filtered and dried.(Yield: 0.782=91%); MS(CI):M+1=288; M+2=289. ##STR88## In Scheme 4above: 2,6-Dichloro-3-nitrotoluene (19)

To a cooled (0° C.) solution of 70% HNO₃ (780 mL) and conc. H₂ SO₄ (360mL) was added a solution of 2,6-dichlorotoluene (18) (0.625 g, 0.88 m)in conc. H₂ SO₄ (360 mL) via a addition funnel over 0.5 hours. Thetemperature was maintained below 5° C. The reaction mixture was kept at0° C. for additional 15 minutes and allowed to warm to room temperature.The mixture was stirred at room temperature for additional 2 hours andpoured onto ice under stirring. The pale yellow solid was filtered andwashed with water until neutral. Crude product was dissolved in EtOAcand 1:1 hexane mixture (1 L) and washed with aqueous NaHCO₃ and water.The organic layer was dried (MgSO₄), filtered and concentrated to give apale yellow solid, 785 g (98%). The product was used as is in the nextstep.

2-Bromomethyl-1,3-dichloro-4-nitro-benzene (20)

To a solution of 1,3-dichloro-2-methyl-4-nitro-benzene (19) (6.18 g, 30mmol) and AIBN (200 mg) in CCl₄ (75 mL), NBS (7.96 g, 45 mmol) was addedunder stirring and reflux. The reaction was monitored by ¹ H-NMR(CDCl₃). Additional NBS (5×7.96 g, total of 270 mmol) was added till thestarting material was consumed. The reaction mixture was filtered hot,and the filtrate was evaporated to dryness. The crude was columnchromatographed (SiO₂, hexanes:EtOAc, 9:1 to 8.5:1.5). The product wasobtained as a low melting white solid: yield 6.869 g, 80%. ¹ H-NMR(CDCl₃) δ 4.75 (s, 2H), 7.45, d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz);MS (CI) m/z 285 (M+H). Anal Calcd for C₇ H₄ BrCl₂ NO₂ : C, 29.51; H,1.42; N, 4.92. Found: C, 29.09; H, 1.43; N, 4.71.

1-(2,6-Dichloro-3-nitro-benzyl)-piperidine (21)

To a solution of 2-bromomethyl-1,3-dichloro-4-nitro-benzene (20) (8.79g, 30.8 mmol) and triethylamine (6.06 g, 60 mmol) in anhydrous THF (50mL), piperidine (2.72 g, 32 mmol) was added at 0° C. under stirring. Thereaction mixture was allowed to warm to room temperature gradually, andthe reaction was monitored by TLC (SiO₂, Hexanes:EtOAc, 1:1). Afterstirring for about 14 hours, the reaction mixture was evaporated todryness, and the product was extracted in EtOAc (250 mL) and washed withwater (2×100 mL) and dried (MgSO₄). The product was purified by columnchromatography (SiO₂, hexanes:EtOAc 95:5 to 8:2) and was obtained as ayellow solid, yield: 7.38 g, 83%, mp 67-68° C. ¹ H-NMR (CDCl₃) δ 1.37(m, 2H), 1.46-1.49 (m, 4H), 2.45 (m, 4H), 3.7 (s, 2H); MS (CI) m/z 290(M+H), 291 (M+2H). Anal Calc for C₁₂ H₁₄ Cl₂ N₂ O₂ : C, 49.85; H, 4.88;N, 9.69. Found: C, 49.86; H, 4.88; N, 9.73.

(3-Chloro-6-nitro-2-piperidin-1-ylmethyl-phenyl)-(4-methoxy-benzyl)-amine(22)

To a solution of 1-(2,6-dichloro-3-nitro-benzyl)-piperidine (21) (0.894g, 3.09 mmol) and triethylamine (0.606 g, 6 mmol) in anhydrous THF (5mL), p-methoxy benzylamine (0.823 g, 6 mmol) was added at 0° C. understirring. The reaction mixture was allowed to warm to room temperatureand stirred for additional 12 hours and evaporated to dryness. Theproduct was extracted with EtOAc (100 mL) and washed with water (2×50mL) and dried (MgSO₄). The product was purified by column chromatography(SiO₂, hexanes:EtOAc, 95:5 to 9:1) as a yellow oil. Yield: 0.81 g, 67%.¹ H-NMR (CDCl₃) δ 1.23-1.26 (m, 6H), 2.23 (m, 4H), 3.63 (s, 2H), 3.76(s, 3H), 3.92 (d, 2H, J=4.4 Hz), 6.65 (d, 1H, J=9.04 Hz), 6.82 (d, 2H,J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz) 7.57 (d, 1H,J=9 Hz), 8.29 (bs, 1H). NOE's were observed from H4 to H3, H5, H6. NoNOE was observed from H4 to H1, which would have been expected if theother regioisomer was formed. MS (CI) m/z 390 (M+1), 392 (M+2).

1-(2-amino-6-chloro-3-nitro-benzyl)-piperidine (24)

To a solution of(3-chloro-6-nitro-2-piperidin-1-ylmethyl-phenyl)-(4-methoxy-benzyl)-amine(22) (0.389 g, 1 mmol) in CH₂ Cl₂ (5 mL) and H₂ O (0.25 mL), DDQ wasadded at room temperature under vigorous stirring. The dark reactionmixture was monitored by TLC (SiO₂, Hexanes:EtOAc, 8:2) and additionalDDQ (0.345 g, 1 mmol) was added. The reaction mixture was filtered afteradditional 2 hours of stirring and diluted with saturated aqueous NaHCO₃solution (100 mL). The product was extracted with CH₂ Cl₂ (2×100 mL),and the extracts were washed with saturated NaCl solution (2×200 mL) anddried (MgSO₄). Dark oil (1.68 g) was chromatographed (SiO₂,Hexanes:EtOAc, 9:1 to 8:2) twice to give the desired aniline derivativeas a yellow solid. Yield: 0.68 g, 25%. ¹ H-NMR (CDCl₃) δ 1.43 (m, 2H),1.53 (m, 4H), 2.38 (m, 4H), 3.75 (s, 2H), 6.6 (d, 1H, J=9.2 Hz), 7.95(d, 1H, J=9.2 Hz). MS (CI) m/z 270 (M+H), 272 (M+2H). Anal Calcd for C₁₂H₁₆ N₃ O₂ Cl: C, 53.44; H, 5.98; N, 15.58. Found: C, 53.76; H, 5.91; N,15.01.

6-Chloro-5-piperidin-1-ylmethyl-1,4-dihydro-quinoxaline-2,3-dione (25)

A suspension of the nitroaniline derivative 24 and Ra Ni (0.2 g) inMeOH/THF was hydrogenated (H₂, 50 psi) in a Parr apparatus. Oncompletion the reaction mixture was filtered, and the filtrate wasevaporated to give a dark viscous oil of the diamine 0.072 g. ¹ H-NMR(CDCl₃) δ 1.4 (m, 2H), 1.49-1.51 (m, 4H), 2.38 (m, 4H), 3.2 (bs, 2H),3.68 (s, 2H), 4.93 (bs, 2H), 6.53 (d, 1H, J=8.3 Hz), 6.61 (d, 1H, J=8.3Hz). MS (CI) m/z 240 (M+H). To a solution of the diamine (0.07 g, 0.3mmol) in THF (2 mL), dimethyl oxalate (0.068 g, 0.58 mmol) was added inone portion under stirring. The reaction mixture was heated to refluxfor 14 hours and allowed to cool to room temperature. The off-whiteprecipitate was then filtered and washed with THF and dried. Yield:0.058 g, 67%. Mp 273-275° C. ¹ H-NMR (DMSO-d₆) δ 1.4 (m, 2H), 1.49-1.51(m, 4H), 2.38 (m, 4H), 3.86 (s, 3H), 6.99 (d, 1H, J=8.5 Hz), 7.12 (d,1H, J=8.5 Hz). MS (CI) m/z 294 (M+H), 295 (M+3H). Anal Calcd for C₁₄ H₁₆ClN₃ O₂ : C, 57.24; H, 5.49; N, 14.3. Found: C, 57.82, H; 4.48; N,13.91.

6-Chloro-7-nitro-5-piperidin-1-ylmethyl-1,4-dihydro-quinoxaline-2,3-dionesulfate salt (26)

To a solution of6-chloro-5-piperidin-1-ylmethyl-1,4-dihydro-quinoxaline-2,3-dione (0.173g, 0.59 mmol) in H₂ SO₄, KNO₃ was added under stirring at 5° C. Thereaction mixture was allowed to gradually warm to room temperature andstirred further for about 14 hours. The dark reaction mixture was thenpoured in ice-water to give a yellow green precipitate, which wasfiltered and washed with ice-cold water and dried. Yield: 0.178 g,69.26%. mp 297-300° C. ¹ H-NMR (DMSO-d₆) δ 1.38-1.47 (m, 6H), 2.44 (m,4H), 3.93 (s, 2H), 7.58 (s, 1H). MS (CI) m/z 339 (M+H), 341 (M+3H). AnalCalcd for C₁₄ H₁₅ ClN₄ O₄. 1.2 H₂ SO₄ : C, 36.98; H, 3.85; N, 12.33.Found: C, 36.98; H, 3.77; N, 12.07. ##STR89##4-Bromo-3-methyl-6-nitro-2-piperidin-1-ylmethyl-phenylamine

A solution of6-bromo-5-methyl-8-nitro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.184 g,0.64 mmol) for 8 hours in piperidine (2 mL) was heated to 110° C. Thedark reaction mixture was evaporated under vacuum and the crude waschromatographed (SiO₂, pet. ether:EtOAc, 9:1→7.5;2.5) to give yellowproduct. (Yield: 0.154 g, 75%); MS(CI):M+1=326; M+2=327.

The intermediate 5 can be converted to the correspondingquinoxaline-2,3-dione derivative by procedures shown in Scheme 1.

Other compounds prepared by methods analogous to the above include butare not limited to: ##STR90##

The above cyclic amines are available from commercial sources. ##STR91##

What is claimed is:
 1. A method of treating convulsions which comprisesadministering a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof, whereinR is amono, bi-cycle spiro ring non-aromatic unsubstituted or substituted byfrom 1 to 4 subtituents, R is attached to the quinoxaline ring through(--CH₂)_(n) and at the a- or b-position and R is ##STR92## of from 4 to7 atom; or ##STR93## of from 8 to 12 atoms wherein R₁₁ is from 1 to 4substituents independently selected fromhydrogen, hydroxy, hydroxyalkyl,alkyl, alkoxy, alkoxyalkyl, --NR₁₃ R₁₄, aminoalkyl, alkenyl, alkynyl,thiol, alkythioalkyl, aryl, aralkyl, heteroaryl, heteroalkyl,cycloalkyl, --SO₂ R₁₅, --SO₂ NR₁₃ R₁₄, --(CH₂)_(n) SO₂ NR₁₃ R₁₄, and--(CH₂)_(n) SO₂ R₁₅, wherein R₁₃ and R₁₄ are independently selectedfromhydrogen, alkyl, cycloalkyl, heterocycle which is a ring with from 4to 7 members, with up to 4 heteroatoms selected from N, O, and S,aralkyl, and aryl; R₁₅ is hydroxy, alkoxy, --NR₁₃ R₁₄, or haloalkyl; R₁₁may be 2 substituents attached at the same carbon; X and Y are eachindependently carbon which is substituted by hydrogen, halogen,haloalkyl, alkyl, alkoxy, alkoxyalkyl, NR₁₃ R₁₄, aminoalkyl, aralkyl,aryl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycle which is a ringwith from 4 to 7 members, with up to 4 heteroatms selected from N, O,and S, hydroxy, hydroxyalkyl, --O--, --S--, --SO--, --SO₂ --, --NR₁₆ --;wherein R₁₆ is alkyl, hydrogen, aralkyl, heteroalkyl, aryl, heteroaryl,cycloalkyl, hetercycle which is a ring with from 4 to 7 heteroatomsselected from N, O, and S, --C(O)OR₁₇, --C(O)R₁₇, --SO₂ R₁₈, --SO₂ NR₁₉R₂₀, --CH₂ SO₂ R₁₈, and --CH₂ SO₂ NR₁₉ R₂₀, wherein R₁₇ is alkyl,aralkyl, cycloalkyl, heterocycle which is a ring with from 4 to 7heteroatoms selected from N, O, and S, aryl, or heteroaryl; R₁₈ isalkyl, aralkyl, hydroxyl, or alkoxy; R₁₉ and R₂₀ are each independentlyhydrogen and alkyl; R₁ is hydrogen,alkyl, aralkyl, carboxyalkyl,phosphoroalkyl, or phosphonoalkyl, R₇ is hydrogen, hydroxy, or amino, R₃and R₄ are each independentlyhydrogen, alkyl, cycloalkyl, alkenyl,halogen, haloalkyl, nitro, cyano, SO₂ CF₃, CH₂ SO₂ R₆, (CH₂)_(m) CO₂ R₆,(CH₂)_(m) CONR₇ R₈, (CH₂)_(m) SO₂ NR₇ R₈, or NHCOR₆ wherein m is aninteger of from 0 to 4, and R₆, R₇, and R₈ are each independentlyselected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R₅ ishydrogen,alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl,heteroaryl, nitro, cyano, SO₂ CF₂, (CH₂)_(m) CO₂ R₉, (CH₂)_(m) CONR₉R₁₀, SONR₉ R₁₀, or NHCOR₉ ; wherein m is an integer of from 0 to 4; R₉and R₁₀ are each independently hydrogen, alkyl, cycloalkyl, or aralkyl;and R₅ may be at the a-position and R--(CH₂)-- at the b-position on thering to a patient in need of said treatment.